Atazanavir bisulfate, also known as (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaaza-tetradecane dioic acid dimethyl ester, sulfate (1:1), and it is represented by the following structure:

Atazanavir bisulfate is marketed under the brand name of REYATAZ and is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. REYATAZ capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate.
U.S. Pat. No. 5,849,911 (“the '911 patent”) discloses a series of azapeptide HIV protease inhibitors such as Atazanavir. The '911 patent further discloses a process for the preparation of azapeptide HIV protease inhibitor Atazanavir by coupling the epoxide with a hydrazine carbamate in the presence of isopropyl alcohol to form the protected diamine, the protected diamine is treated with HCl to form diamine, the diamine is isolated and coupled with N-methoxycarbonyl-L-tert-leucine to obtain Atazanavir free base.
The process disclosed in the '911 patent is schematically represented as follows:

In the '911 patent, atazanavir methane sulfonate is precipitated with ether from methylene chloride solution thereof followed by drying under reduced pressure; whereas atazanavir hydrochloride is precipitated by mixing dioxane solution of atazanavir with dioxane solution of hydrochloride. However this patent remains silent about the sulfate salt preparation.
U.S. Pat. No. 6,087,383 (“the '383 patent”) discloses atazanavir bisulfate and process for the preparation of the same in two crystalline polymorphs such as Type-I and Type-II crystals. The '383 patent further discloses that the Type-I crystals are anhydrous/desolvated crystals whereas the Type-II crystals are hydrated, hygroscopic crystals. The Type-I crystals are prepared by adding sulfuric acid in to a suspension of atazanavir free base and a solvent such as acetonitrile, ethanol-heptane or acetone followed by seeding the crystals. The Type-II crystals are prepared by adding sulfuric acid in to a suspension of atazanavir free base and isopropanol chilled in an ice-bath, stirring the suspension at room temperature and seeding Type-I crystals.
Organic Process Research and Development, 6, p. 323-328 (2002) describes the preparation of Type-I crystals of atazanavir sulfate by adding sulfuric acid in to a solution of atazanavir free base in ethanol and then adding n-heptane and seed crystals.
Organic Process Research and Development, 12, p. 69-75 (2008) discloses crystallization of atazanavir free base with ethanol-water solvent system.
U.S. Pat. No. 7,829,720 (“the '720 patent”) discloses an improved process for the preparation of Atazanavir bisulfate Form A crystals (which are referred to as Type-I crystals in US '383 patent) by a modified cubic crystallization technique in which sulfuric acid is added at an increasing rate according to a cubic equation, a relatively larger, more well defined atazanavir bisulfate crystals, along with a narrower particle size range and fewer fines are provided, than a constant addition rate crystallization. The '720 patent described that the crystal particle size and morphology of the atazanavir bisulfate salt are dependent on the addition rate of the sulfuric acid, which determines the crystallization rate.
The '720 patent process includes the steps of reacting a solution of atazanavir free base in an organic solvent (in which the atazanavir bisulfate salt is substantially insoluble) with a first portion of sulfuric acid in an amount to react with less than about 15%, by weight of the atazanavir free base, adding seeds of atazanavir bisulfate Form A crystals to the reaction mixture, adding additional sulfuric acid in multiple stages accurately at increasing rates according to a cubic equation to effect formation of Form A crystals.
U.S. Pat. No. 8,461,347 (“the '347 patent”) discloses an improved process for the preparation of Atazanavir bisulfate Form A crystals by solvent and antisolvent method.
The processes for preparation of Atazanavir bisulfate described in the above literature have certain drawbacks as it involves either formation of undesired crystals by standard addition of sulfuric acid or formation of desired Form A crystals by incorporating special limitations such as calculated quantity of acid addition at different increasing intervals at a specific time intervals and at a specific temperature in order to achieve controlled crystallization, which are not viable and burdensome for those of ordinary skill in the art, particularly in commercial scale operations.
Hence, there remains a need in the art for an improved process to prepare pharmaceutically desirable Atazanavir bisulfate Form A crystals, which is feasible at large scale, in terms of ease and cost-effective. The inventors found an improved process for preparing atazanavir Form A crystals under controlled crystallization conditions, where the improvements include additional sulfuric acid is added in a continuous manner without involving aforementioned limitations.